A 2002 patient survey conducted by the Ministry of Health, Labor, and Welfare of Japan revealed that the total number of patients with diabetes was 2,280,000 in Japan. A diabetes research conducted in the same year estimated that the number of patients strongly suspected of having diabetes and the number of patients for whom the possibility of diabetes could not be denied add up to 16,200,000.
As far as the domestic market is concerned, Japanese have a genetic factor for decreased insulin secretion and, thus, defective insulin secretion predominates. However, an increasing number of patients are suffering from insulin resistance due to the recent shift to western diets. Thus, there is a need for drugs that are effective against both defective insulin secretion and insulin resistance.
Glucokinase (GK) is an enzyme that catalyzes phosphorylation of glucose. The enzyme acts as a glucose sensor in the body by promoting insulin secretion and glucose utilization in liver in response to high glucose levels. Since whole-body glucose homeostasis is not maintained in diabetic patients, activation of GK in these patients can reduce the blood glucose levels by facilitating glucose-dependent insulin secretion in pancreas and by facilitating glucose utilization in the liver or suppressing glucose release from the liver (dual action) (Non-Patent Documents 1 through 3). Effective against both defective insulin secretion (pancreatic action) and insulin resistance (hepatic action), GK activators are considered an ideal treatment for diabetes.
Among known GK activators are a variety of amide compounds (Patent Documents 11 through 19), including arylcycloalkylpropionamides (Patent Document 1), 2,3-disubstituted trans olefinic N-heteroaromatic ring- or ureido-propionamides (Patent Document 2), alkynylphenyl heteroaromatic amides (Patent Document 3), hydantoins (Patent Document 4), substituted phenylacetamides (Patent Document 5), para-alkyl-, alyl, cycloheteroalkyl-, or heteroaryl-(carbonyl or sulfonyl)amine-substituted phenylamides (Patent Document 6), alpha-acyl and alpha-heteroatom substituted benzeneacetamides (Patent Document 7), tetrazolyl phenylacetamides (Patent Document 8), fused heteroaromatic compounds (Patent Document 9), and phenylacetamides having a cycloalkane with a single carbon atom substituted or a heterocyclic ring (Patent Document 10). However, no reports have described GK activators in which two fluorine atoms are attached to different carbon atoms of a cyclopentyl group.    Patent Document 1 WO2000/058293 pamphlet    Patent Document 2 WO2001/044216 pamphlet    Patent Document 3 WO2001/083465 pamphlet    Patent Document 4 WO2001/083478 pamphlet    Patent Document 5 WO2001/085706 pamphlet    Patent Document 6 WO2001/085707 pamphlet    Patent Document 7 WO2002/008209 pamphlet    Patent Document 8 WO2002/014312 pamphlet    Patent Document 9 WO2002/046173 pamphlet    Patent Document 10 WO2003/095438 pamphlet    Patent Document 11 WO2004/052869 pamphlet    Patent Document 12 WO2004/072031 pamphlet    Patent Document 13 WO2004/072066 pamphlet    Patent Document 14 WO2005/103021 pamphlet    Patent Document 15 WO2006/016174 pamphlet    Patent Document 16 WO2006/016178 pamphlet    Patent Document 17 WO2006/016194 pamphlet    Patent Document 18 WO2006/059163 pamphlet    Patent Document 19 U.S. Pat. No. 6,911,545    Non-Patent Document 1 Diabetes 45, 223-241 (1996)    Non-Patent Document 2 Diabetes 41, 792-806 (1992)    Non-Patent Document 3 FASEB J. 10, 1213-1218 (1996)